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I was watching the X-Files last night — because bing-watching 1990’s television is how I opt to spend my free time — when the show mentioned a particular analytical technique readers will be well familiar with: NMR.

One of the reasons I love this show so much is because the blatant pseudo-science presented has a glimmer of real science somewhere embedded in it. Sure it’s fiction; but I’ve never seen them put up a structure containing a Texas carbon (and I’ve been looking!).

In last night’s episode, Special Agent Dana Scully shows her partner, Special Agent Fox Mulder, a “nuclear magnetic resonance spectra [sic].” This then comes on screen for a couple seconds (click to embiggen):

Screen cap from The X-Files S4E19 “Synchrony”, approximately 14:30 into the episode

A Proton NMR spectrum indeed! The protagonist explains the analyte in question is a drop of blood from a murder victim; that’s an awfully clean spectrum from such a complex source. The compound we are looking at is an experimental super toxin which “catalytically” induces freezing — and subsequent death — in it victims.

Obviously, no such catalyst exists, but this is a real NMR spectrum of something. The solvent appears to be deutero-chloroform spiked with TMS. There’s an aromatic signal almost directly on top of the chloroform singlet. It gets complicated in the 6.5-5.5 region with olefins aplenty. A singlet at ~4.1 could belong to some kind of substituted anisole, or a chloromethyl group? The doublet at 3.3 has me stumped. My first guess would be methylene adjacent to NH, but alas, no NH proton visible. Down around 2-1 ppm we have a mess of methyl groups and what looks like a t-butyl at 1.2 ppm.

I am awarding a bounty of 10 internet points to the commenter who can propose the most plausible structure for this spectrum. For historical context, the episode was filmed in 1996-97 in Cambridge, MA using MIT for some of the shots. So it’s a possibility that the spectrum was pulled from an MIT lab.

A couple weeks ago, I talked about a patent published by the Klapötke group in which a series of bis(aminotriazole) salts were prepared and characterized. It’s pretty neat stuff, and the molecules showed pretty solid energetic performance across the board.

Well, as luck would have it, another publication from the same group came out last week. This piece is a followup on some chemistry from back in 2015 [1], wherein they prepared some triazole tetrazoles bearing nitro, azido, and amino ring substituents (compounds 5–8). You know, for the severely carbon-averse out there. A quick snapshot of this chemistry is reproduced below. Compound 5 is afforded in ~64% overall yield in 5 steps. The process chemists out there will appreciate this detail: all compounds are prepared by chromatography-free means.

Get your azoles, now with 33% more nitrogen! — Reproduced from [1]

As one might expect, the sensitivities of the four parent compounds to external stimuli (impact, friction, ESD) ranged from “quite” to “extremely.”

The scope of the recent offering is to use these materials as energetic anions with various metallic and non-metallic cations [2]. Since the tetrazole proton is basically holding on for dear life — as evidenced by a 1H chemical shift of 16.19 ppm — preparing these salts was a matter of treating the parent compounds with a basic solution of the desired cation. The goal here being use metal cations (a–c) to produce sensitive primary explosives, and nitrogen-rich cations (d–h) to produce less sensitive secondary explosives.

Silver’s an interesting choice; I’m generally content to not find myself in the same room as large quantities of any compound with both “azido” and “silver” in its name, but nonetheless, compound 6c exists, albeit only briefly. The compound has impact and friction sensitivities below the minimum test threshold using the BAM method. To quote the text:

The yield [of 6c] was not determined owing to the extremely high friction sensitivity of this compound.

The cesium analog, 6b, fares slightly better. It holds together long enough to get some spectroscopy data, and the impact, friction, and ESD sensitivities of this compound were high, but measurable. The text notes the ESD value is slightly less sensitive than lead azide, which is commonly employed in blasting caps. But high sensitivity alone does not necessarily make for a good primary explosive — the material must be capable of initiating detonation in a secondary explosive. To that end, a mass of RDX was loaded into a copper tube sealed at one end, and 50 mg of compound 6b was layered on top. Firing with an electrical detonator resulted in the image below:

So it does in fact kick off secondary explosives quite nicely — fragments of metal casings are often a welcome sign in energetic research. It is also noted that compounds 6a–c all undergo a deflagration to detonation transition (DDT), although it’s not clear how this was determined. Small samples of explosives generally do not detonate unless they are confined or there is a critical diameter present. But I digress.

Now onward to the so-called “nitrogen rich” salts. A total of 14 nitrogenous salts were prepared, however four were only isolable as the corresponding dihydrates: 5d, and 8-2e–g (compound 8 formed the corresponding dianion). The remaining ten demonstrated a very high degree of insensitivity. With the exception of 7e, all were less sensitive than RDX in BAM impact and friction, and ESD tests. Additionally, all were within a 10% margin of RDX in both detonation velocity and detonation pressure according to EXPLO5 calculations. Likewise, almost all burned cooler than RDX.

One major advantage of using nitrogen-based HEDMs is that they are non-oxidative. That is, no oxidizing salts (say, perchlorate, nitrate), and minimal organic nitro-groups, so metal components of gun barrels won’t break down as quickly. Since deflagrations/detonations are far from ideal from a stoichiometry standpoint, you can end up with significant amounts of NO and NO2 (and even HCl if your propellant is ammonium perchlorate). Those gases get pretty warm in armament combustion chambers and can seriously damage barrel bores, which can lead to critical failure. But with nitrogen heterocylces, you reduce the formation of nitrogen oxides and instead form mostly N2, and eliminate chlorine entirely.

So to that end, the authors reformulated two propellants, HN-1 and HN-2 (HN = “High nitrogen”), which are used in very large bore guns. The compositions are mostly RDX, with some TAGzT, a relatively sensitive triaminoguanidinium salt of 5,5′-azotetrazole. Substituting compound 5h, for TAGzT resulted in about a 10% boost in the specific energy of the formulation, with a modest increase in combustion temperature.

This is a perfect example of one of the fundamental challenges of energetics research, which I mentioned in passing in my previous post: you can’t have it all. You can always cram more energy density into a molecule — just stick more nitro groups on it, or replace a triazole with a tetrazole. But increasing the energy density comes at a price, almost without exception: your molecule burns hotter, or is more sensitive, or both. And the authors acknowledge this, stating that while the combustion temperature increases, it is still well below the critical temperature for gun propellants.

The Klapötke group at LMU is marching relentlessly onward with their quest to find new and interesting ways to stick as many nitrogen atoms onto one molecule in as close proximity as (barely) possible for long enough to get NMR data.

You may remember the Klapötke group from Derek’s post over at ItP in the “Azidoazide Azide” issue of Things I Won’t Work With. This is the group that would look at pentazole and think “Gee, I wonder if we could replace that proton with an azide…” I’ve always thought this kind of work was pretty cool; most of these crazy nitrogen heterocycles are practically useless but they serve the important purpose of giving us a better understanding of the nature of chemical bonds at the margin of what is possible.

Klapötke et al is back with a published patent application that showed up on my scanner. This time, they’ve taken a step back from the realm of the ridiculous and have prepared a reasonable looking energetic active ingredient: 3,3′-dinitro-5,5′-bis-triazole-1,1′-diol (and a couple bis salts thereof).

And that structure looks not at all unreasonable. Sure, electron deficient triazoles aren’t the most stable, but that hydroxyl contributes some electron density back to the ring system. Oxygen balance looks good. Slightly under-oxidized, actually, which as a rule gives you a bit of stability back.

But enough with speculation, let’s take a look at the thermal and sensitivity data provided in the text. In energetics, RDX is commonly used as a benchmark: it has good (not great) explosive performance, and it reasonably insensitive to impact, friction, and electrostatic discharge. Interestingly, the application does not present characterization data on the parent diol, but instead offers three salts: dihydroxylammonium (MAD-X1), diguanidinium (MAD-X2), and di-triaminoguanidinium (MAD-X3).

And the lead compound, MAD-X1, outperforms RDX across the board: better sensitivity in all three metrics, high detonation velocity (9.3 km/s to RDX’s 8.7), greater crystal density, higher thermal decomposition onset, larger heat of formation, and lower detonation temperature. As anyone who works in the field knows, it’s really hard to have it all; you can always increase you explosive performance… at the expense of sensitivity. And vice versa. But, as far as performance metrics go, MAD-X1 seems to pretty handily have a leg up on the competition.

Even the synthesis is pretty straightforward and uses decidedly non-exotic reagents. First, oxalic acid is condensed with aminoguanidinium bicarbonate in concentrated HCl, then worked up under basic conditions, affording 3,3′-diamino-5,5′-bis-(1H-1,2,4-triazole) (“DABT”). DABT is then oxidized to the bis-nitro derivative as the corresponding dihydrate, which is fantastic from a energetics processing standpoint. Treatment with potassium peroxymonosulfate affords the anhydrous diol, which reacts subsequently with an ethanolic solution of hydroxylamine, which yields MAD-X1 in 44% overall yield over four steps.

While not as concise as the two-step Bachmann process, which yields RDX from hexamethylenetetramine in 57% overall yield on an industrial scale, Klapötke’s preparation of MAD-X1 appears scalable. Namely, it dispenses with the wildly exothermic nitrolysis process used to make nitramines — if you’ve ever had the pleasure of performing such a reaction you’ll know it’s incredibly easy to end up with a runaway reaction and a resultant yield rapidly approaching zero. Do that on a large scale, and you’ll have a pilot plant rapidly approaching low earth orbit.

Overall, I’m pretty impressed with this compound’s prep and apparent utility. My main criticism is: how’s that alkoxide salt going to hold up in an environment where metals are present? Namely, in a casing or shell. If the the use of picric acid has taught us anything, it’s that acidic energetics tend to not play well with metals. I’d love to see some followup formulation work addressing this issue.

Last night, I was killing some time while waiting for a particularly stubborn 13C-NMR experiment to run by browsing through my company’s library. I came across something particularly interesting there; everyone knows Fieser and Fieser’s classic Reagents for Organic Synthesis, but did you know before that series was published, the duo authored a first-year organic chemistry text book? That’s right, I found an original 1950 edition of Louis and Mary Fieser’s Textbook of Organic Chemistry.

It’s got some really beautiful illustrations, and some discussions you’d probably not find in a more modern o-chem book. I thought the readership here might appreciate some of the artwork:

The cover, complete with debossed gold lettering

We open with electron shells:

Argon was represented by “A” until 1957

Soon, we are met with a discussion about the structure of benzene. Correctly ascertained in 1865, the Fiesers present a short history of alternative benzene structures:

Structural elucidation was a laborious task in the early-to-mid 1900’s. FT-IR was only just discovered in the late 1940’s, and it wasn’t until the 1960’s that is was widely available as a characterization tool. Without mass spectrometry and NMR, chemists had to rely largely on elemental analysis:

A CH combustion analysis apparatus

The principals of stereochemistry were known, and optical rotation could be determined using a polarimeter. Chemists were still a ways off from the digital polarimeters used today:

The text describes a method for hydrogenation of olefins at atmospheric pressure in elegant style:

And distillation:

Next up, my favorite part: a short section on explosive chemistry. Although those picrates land squarely in the category of things I won’t work with:

And did you know that the first chemotherapeutic agent was an organoarsenic compound? The text describes the synthesis of arsphenamine, a treatment for syphilis in the early 1900’s, until it was supplanted by the much safer and more efficacious penicillin.

And check out these subsequent illustrations of steroids and the heme group from hemoglobin:

There’s a Q&A piece in Current Biology (a Cell journal) on Professor Jingmai O’Connor circulating at the moment. Most of it it pretty standard stuff: Why are you a biologist? What’s it like being an American scientist in China? What was your favorite conference?

But for a “young scientist,” two of O’Connor’s answers sure seem old school. One question asked of the professor was “Do you think there is an increased need for scientists to market themselves and their science as a brand?” Her answer (emphasis mine):

I think the idea that scientists need to operate more like a business is becoming a major problem in science recently. There is science and there is business — they are different and should be fundamentally driven by different goals: one, the pure and unadulterated desire for greater knowledge and the other, monetary gain. Branding science puts focus on making your research appealing, which is extremely limiting, and — dare I say? — corrupts the scientific process. There is a lot of fundamental research that needs to be conducted that is not ‘sexy’. Such ‘science branding’ has not yet affected the Chinese Academy of Sciences and for that I’m grateful.

Ignoring how pretentious this comes off as, the idea that making your science “appealing” somehow corrupts it is exactly wrong. Science should be appealing. If your science isn’t appealing, maybe you’re not doing good science. And second, the idea that business and science are mutually exclusive enterprises is laughable. I can point to dozens of fundamental scientific discoveries made by the private sector. It turns out that money is actually a pretty good motivation for coming up with cool new scientific ideas. Conversly, let’s not pretend that all science is driven by “the pure and unadulterated desire for greater knowledge.” This implies that only academic science is true science. But even academic science has a driving force that is decidedly non-scientific.

It gets better (worse?) from here. “What’s your view on social media and science? For example, the role of science blogs in critiquing published papers?”

Those who can, publish. Those who can’t, blog. I understand that blogs can be useful in affording the general public insights into current science, but it often seems those who criticize or spend large amounts of time blogging are also those who don’t generate much publications themselves. If there were any valid criticisms to be made, the correct venue for these comments would be in a similar, peer-reviewed and citable published form. The internet is unchecked and the public often forgets that. They forget or are unaware that a published paper passed rigorous review by experts, which carries more validity than the opinion of some disgruntled scientist or amateur on the internet. Thus, I find that criticism in social media is damaging to science, as it is to most aspects of our culture.

Damn kids, get off my lawn!

That’s a real doozy. The last part reads like that guy who is proud of not having a Facebook account like it’s some sort of accomplishment. But all snark aside, I strongly disagree fundamentally with what O’Connor has to say about blogging and social media with respect to science. I can point to example after example of successful, productive scientists with active social media presences. Again, the two are not by any means mutually exclusive.

But perhaps my biggest problem with this response is how brazenly the author dismisses public criticism and post-peer review in favor of the almighty peer review process. As if nothing shady ever gets by peer reviewers. If you publish something in the scientific literature, you’re putting your work out there. You’re making claims, and you shouldn’t be surprised (or offended) when challenges are made to what you’ve said. Because challenging the status quo is exactly how science works, whether it’s in a subsequent publication, a blog, or on PubPeer.

I’m here to talk about why science is so expensive. This was prompted by the recent news regarding Turing Pharmaceuticals, led by CEO Martin Shkreli. Turing recently acquired exclusive rights to manufacture and sell pyrimethamine, an off-patent drug used primarily to treat parasitic protozoan infections. In a move which Ayn Rand herself would probably describe as “heavy-handed,” Shkreli has opted to increase the price of the drug over fifty-fold overnight*, somewhat disconcerting considering it’s used to keep AIDS patients from, you know, dying.

The issue garnered international attention, with many (many) calling this an example of the absurd pricing power granted to the pharmaceutical industry. Except it’s really not a par for the course industry move, and just as many industry insiders are condemning the price hike. I won’t delve into the details, as plenty of others much more knowledgeable than I already have. I’m also not going to beat the “drug research is expensive” dead horse (spoiler: it is). The point is, many people seem to cry foul**; “There’s no way R&D can be that expensive!”

Instead, I’m going to talk about why science in general is so expensive (second spoiler: it is) and where the associated costs come from. Television seems to have popularized the idea of a genius scientific duo working in tandem and checking off a major scientific breakthrough (bioweapon vaccine, invisibility suit, quantum ion machine gun, etc.) in a montage-filled afternoon. Unfortunately, that idea doesn’t mesh well with reality.

Science Cannot Exist in a Vacuum

Let’s start by examining the core of what science is, as an ideal. What is science? I’d argue that the answer to that question is quite simple: science is discovering new things and telling others about those discoveries. That’s it.

All the impact factors, intellectual property, marketing, and publications? Those are politics, or business; consequences of science, but decidedly not science.

What’s it take to do science? Fundamentally, a scientist, of course. You can’t research new materials without chemists, you can’t map the universe without astrophysicists, or the genome without geneticists. But it turns out, you also can’t map the universe without computer scientists. Likewise, you probably need a few synthetic chemists somewhere along the line to make probes for your geneticists.

Eighteenth century science could be done by a single bowtie-clad bearded guy with sufficiently deep pockets. But modern science cannot. Modern science is collaborative by nature. To the scientists reading, this is a point I shouldn’t need to argue. In the past week alone I have collaborated with: several materials scientists, a biologist, an inorganic chemist, a couple laser specialists, and at least one battery scientist. And that’s not even an exhaustive list.

In order to properly do my job, I need to be surrounded by a dozen or so other scientists, who in turn, each need a dozen or so to support them. My company employs in the ballpark of 100 scientists, and I’ve worked with almost all of them at one time or another.

And that’s where the baseline cost of doing science comes from. To do science, you need a network of scientists. How big that network needs to be depends on how complicated and diverse the problems you are working on are. And as much as we scientists generally love doing science, we don’t do it for free.

Scientists Need Tools

This seems obvious, but most non-scientists probably haven’t stopped to consider how much scientific equipment costs. And I’m talking capital equipment, not stuff that gets used up like glassware and reagents.

Consider: I operate a Varian 300 MHz NMR spectrometer on a daily basis. It’s an old instrument, but it’s in excellent working condition. Despite being old, it still takes time and money to keep it up and running. How much do you think it costs to operate for a year? When you consider the service contract, preventative maintenance, cryogens, and time, I think it’s safe to say that it’s more than I make in a year. And that’s a fixed cost; if I use it every single day, or if it sits in it’s air-conditioned room as a giant paperweight, that cost is the same.

Now imagine a larger company which may operate several such instruments. They’d almost certainly have at least one full-time scientist charged with maintaining them, and that’s on top of the other costs.

And an NMR is actually a pretty simple instrument to take care of. If you’ve got an LC/MS (a modern triple-quad will run around $150k), you now have tons of additional operating costs to consider, and you probably need one technician per 2-3 instruments just to keep them operational. Same goes for GC/MS.

If you’re a materials scientist, you need an electron microscope. Those cost a pretty penny. Plus, they pull huge amounts of power to run. If you’re doing any serious biology experimentation, you probably need a decent confocal microscope. I have it on good authority that a single lens for one can set you back tens of thousands of dollars.

Power, service contracts, technicians, software licenses, instrumentation. Everything adds up, real quick. You could buy a townhouse for the cost of an 800 MHz NMR spectrometer.

In addition to the tools, you need a place to do science. Fume hoods, bench space, ventilation. You’ve got to keep the lights on and water flowing, and pay the building’s rent. When you spend money on science, you’re spending money on this infrastructure, all of which needs to be paid for somehow.

Consumables

Now you’ve got a sufficiently large group of interdependent scientists, all under the same roof, and all standing around with shiny new tools and instruments. But they still need stuff to work with, and that means spending money on consumables. Glassware, solvents, reagents, gases. If you’re of the biological persuasion, cells and animal models. And all of those are sold at a premium, because remember all that infrastructure I talked about earlier? Yeah, the companies supplying researchers have all of that to deal with too, plus the added costs of manufacturing, quality assurance, regulatory compliance and shipping logistics.

All that means that a pair of scissors from Sigma Aldrich costs roughly fifteen times what it would cost at Staples. But really, that’s just a somewhat egregious example that non-scientists can get their head around. I’ve ordered my share of compounds which cost upwards of a thousand dollars for one milligram. I’ll go through almost a 4-liter jug of acetone in a week, a liter or so of DCM, chloroform, or any of half a dozen other common solvents. And if you’re running a lot of NMR (like I am) you’re going to chew through deuterated solvents, which cost around ten times what their isotopically abundant counterparts do.

Working with living organisms? Well now everything, reagents included, needs to be sterile, which takes time and energy and is passed on to you in the form of higher prices.

Plus everything needs to be disposed of, and as you’re probably aware, you can’t just pour your reactions down the sink when you’ve finished with them. Having chemical and biohazardous waste disposal companies on call to haul out the stuff you buy costs money too, sometimes even more than the cost of the stuff you originally bought (I’m looking at you, old lecture bottles).

Time, Time, and More Time

Those of you personally familiar with the scientific process will be intimately aware of the single largest cost of doing research: time. Time is money, and science takes a lot of time. Much, much more often than not, research leads to failure, which leads to slightly more informed failure, which, if you’re persistent and lucky might lead to success. That’s not the fault of the researchers, that’s just the way it is.

And in order to do experiments, even ones that will invariably fail, you still need all those consumables talked about earlier. I recently attempted to prepare a compound according to a slightly modified literature procedure that involved bubbling a fluorinated, gaseous compound through an anhydrous ammonia solution. And guess what? It didn’t work. By all accounts it should have, but hey, research. Over a thousand bucks for a cylinder of specialty gas, another couple hundred for the solvents and ammonia. An entire day of careful planning and preparation. And all of that gone in one shot on a failed*** experiment. I had to order everything again, modify my procedure, and try again; the second time turned out to do the trick.

The point is: it cost twice as much in materials, took more than twice the amount of my time as originally planned, and set my progress back a week. And that’s just a single experiment in the context of a much larger research program. When you consider that even a modestly sized research program will have several scientists performing related but independent experiments, each of which carries a significant risk of failure, it’s easy to see how much time things can really take.

And that’s OK, because failure is a feature of the scientific process, not a bug. Science cannot progress without failure. Most of the time there’s really nothing that can be done about it, even under ideal conditions; sometimes things just don’t work. But what many don’t realize is that failure incurs the same costs as success, and it takes a lot of failure to get to point where you can call a research program “successful.”

Ultimately this is why emergent technologies are so expensive. This is why you see new drugs which cost close to $100,000 for a course of treatment. It’s because for each Sovaldi, there were hundreds (or thousands) of candidate compounds which didn’t make the cut for one reason or another. Every one of Tesla’s high-capacity lithium metal oxide batteries sold will be covering the cost of the undoubted thousands of experiments which led to their development.

_________________________________

*They’ve since back-peddled a bit on the exact price point, but not before very harsh and very public backlash

**To be clear, Shkreli and his ilk don’t seem to be doing any actual research with their profits

***There are no failed experiments, only new ways not to make the compound in question

Oh dear. Well, It didn’t think I’d have cause to write about methamphetamine production again, but here we are. Many readers will have heard news about the explosion that rocked the NIST lab near Washington, D.C. back in July. Luckily, no one was seriously injured; but one security guard did sustain some burns.

No more than a couple days later, initial investigations revealed the cause of the explosion appeared to be… methamphetamine synthesis. Now, any competent chemist in a national lab would (hopefully) be able to perform any of the common meth syntheses without incident. Certainly without blowing the windows out of the building and hospitalizing his or herself.

But as it turns out, the culprit wasn’t a chemist, but the security guard injured in the blast. More details have been emerging since the incident. After resigning from the force, the guard in question pled guilty to attempted methamphetamine manufacture.

It turns out the method the guard was attempting to employ is that known colloquially as the “Shake and Bake” method. This involves reduction of pseudoephedrine to methamphetamine, then treatment of the reaction mixture with hydrochloric acid, forming a salt which is easily separated. And in true MacGyver style, the reagents used in this reduction are all improvised: camping stove fuel as a solvent, lithium from batteries, lye, and ammonium nitrate (fertilizer). HCl is generated by the action of sulfuric acid (sold as drain cleaner) on table salt. Literally everything you need can be purchased at Wal-Mart.

And what do we do with these reagents? Why, toss them in a water bottle, close the cap, and shake, of course. You can’t hear it, but I’m actually screaming behind my keyboard.

The idea is you vent the bottle, as a good amount of gas is going to come off of that particular reaction. The reason people use this method to make meth, aside from easy access to the starting materials, is that it can be done on a very small scale: a few grams.

What I don’t understand is why, if you’re going to illicitly make methamphetamine in a synthetic chemistry lab, you decide to bypass all those fancy solvents, reagents, glassware, and safety equipment. Maybe they were worried someone was taking inventory of the reagents they’d need? In my experience, it’s highly unlikely anyone was.

Instead of doing some homework and using the lab equipment that was already right there, they opted to go straight to the basement-bottom chemistry.

And again, I can only speculate as to exactly what caused the explosion (chemists: take your pick of things that could go wrong with that procedure), but I’d put money on overpressure in the “reaction vessel,” resulting in rupture, and exposure of lithium to air. That would likely generate enough heat to ignite the expanding camp-fuel-solvent cloud. And ka-boom.